The ability to accomplish and develop complex cognitive and motor tasks depends on the accuracy and intricacy of synaptic connections both within the cerebral cortex and between the cortex and other regions of the brain. Axonal projections of excitatory projection (pyramidal) neurons constitute the motor output of the entire cortex and directly influence behavior. Molecular mechanisms regulating the molecular identity and connectivity of distinct cortical projection neurons are being unraveled. Our goal is to identify mechanisms that are important for the migration, molecular identity and connectivity of pyramidal neurons, and to investigate their functional roles using a variety of molecular and genetic approaches. Our published and preliminary studies, supported by this grant in the last four years, have functionally characterized several genes encoding transcription factors and axon guidance that control different aspect of cortical projection neuron development, such as their molecular identity, laminar position, dendritic arborization, and axonal projections. In this application we intend to further characterize the cellular and molecular mechanisms by which some of these genes function. Specifically, the proposed experiments are designed to determine how Sox5 controls early-born subcortical projection neurons migration to their proper laminar positions and extend axonal projections (Aim1);how layer-specific expression of Fezf2 and subsequently the molecular identity of projection neurons are controlled cell-intrinsically by upstream transcriptional regulators (Aim2);and how formation of axonal connections with subcortical targets, such as the thalamus, controls gene expression cell-extrinsically in cortical projection neurons during late embryogenesis (Aim3). PUBLIC HEALTH RELEVANCE: The identification of genes and molecular mechanisms involved in the formation and maturation of the cortical circuits as outlined in this proposal will help in understanding normal human brain development and plasticity as well as the neurobiological foundations of developmental and cognitive brain disorders such as mental retardation, schizophrenia, autism, and language impairment. This research may further facilitate the identification of disease genes and the development of new therapeutic strategies for the treatment of these disorders.